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Synthesis of azaphenanthridines via anionic ring closure
Tetrahedron 61 (2005) 9955–9960
Synthesis of azaphenanthridines via anionic ring closure Henriette M. Hansen, Morten Lyse´n, Mikael Begtrup and Jesper L. Kristensen* Department of Medicinal Chemistry, Danish University of Pharmaceutical Sciences, Universitetsparken 2, 2100 Copenhagen, Denmark Received 13 June 2005; revised 25 July 2005; accepted 11 August 2005 Available online 29 August 2005
Abstract—A new and convergent synthesis of azaphenanthridines via an anionic ring closure is reported. Ortho-lithiation/in situ borylation of cyanopyridines produces the corresponding cyanopyridylboronic esters, which undergo a Suzuki–Miyaura cross-coupling to give the key intermediates. Addition of lithium morpholide produces the azaphenanthridines. q 2005 Elsevier Ltd. All rights reserved.
1. Introduction We have previously reported a convergent synthetic protocol for the synthesis of 6-substituted phenanthridines (2) from biaryl 1 (see Scheme 1).1 The reaction proceeds via attack of a lithiated species on the cyanogroup in 1 followed by intramolecular nucleophilic aromatic substitution of the fluorine.
Substituted azaphenanthridines have a broad spectrum of biological activities, including antimalarial2a–c and analgesic activity.2d Furthermore, the 8-azaphenanthridine ring system in 3c is the backbone of the pyridoacridine alkaloids,2e which exhibit anti-bacterial, anti-viral, anticancer activity,2f thus, a short and convergent approach to these ring systems would be highly desirable. Numerous different approaches to azaphenanthridines have been reported in the litterature,3 but all lack the flexibility to produce all the targeted isomers in this study.
2. Results and discussion
Scheme 1. Synthesis of 6-substituted phenanthridines via anionic ring closure.1
The retrosynthetic strategy is exemplified for the synthesis of 3a from biaryl 4a, which in turn should be accessible from commercially available 2-chloronicotinonitrile (5a) via a Suzuki–Miyaura cross-coupling4 (see Scheme 2).
We were interested in expanding the scope of our approach to the synthesis of heterocyclic phenanthridine derivatives, and set out to investigate whether it would be possible to synthesize the four isomeric 6-morpholinoaza-phenanthridines 3a–d shown in Figure 1 using this strategy. Scheme 2. Retrosynthetic analysis of 3a.
Indeed, coupling of 5a with the depicted 2-fluorophenylboronic ester5 gave biaryl 4a in 95% isolated yield (see Scheme 3). Figure 1. Targeted azaphenathridines. RZmorpholine. Keywords: Pyridines; Lithiation; Anionic ring closure. * Corresponding author. Tel.: C45 35306487; fax: C45 35306040; e-mail: [email protected] 0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.tet.2005.08.051
With the desired biaryl in hand we were ready to test the proposed ring closure. Treating 4a with lithium morpholide at reflux yielded a 37:63 mixture of the desired azaphenanthridine 3a together with 6 resulting from nucleophilic
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Scheme 3. Synthesis of 4a.
sequence of cyanopyridines.9 Submitting 2-, 3- and 4-cyanopyridine to our standard conditions for in situ trapping with LiTMP/B(OiPr)3 produced the desired cyanopyridylboronic esters 5b–d in 52–94% isolated yield (see Scheme 5). In all cases, GC–MS of the crude material showed full conversion to the desired cyanopyridylboronic esters.
Scheme 4. Addition of lithium morpholide to 4a.
aromatic substitution of fluorine by lithium morpholide6 (see Scheme 4, entry 1). We speculated that coordination of lithium morpholide to the pyridine nitrogen was a prerequisite for the direct nucleophilic substitution as seen in the work by Meyers and co-workers on nucleophilic aromatic substitution on 2-fluoro-aryloxazolines.7 If this coordination could be impeded, perhaps the ratio between 3a and 6 would increase. Repeating the experiment with 2 equiv of DMPU8 did improve the ratio (see Scheme 4, entry 2) and 5 equiv of DMPU accentuated the effect even more to give a 83:17 mixture of 3a and 6 (see Scheme 4, entry 3). Increasing the amount of DMPU did not influence the ratio further and let to a decrease in conversion. LiCl was tried as additive in an attempt to pre-complex the pyridine nitrogen, preventing lithium morpholide from coordinating, and the result was remarkable (see Scheme 4, entry 4). With 5 equiv of LiCl the desired product was the only detectable species, and 3a was obtained in 84% isolated yield.
Scheme 5. Synthesis of cyanopyridylboronic esters 5b–d.
2.2. Cross-coupling of cyanopyridylboronic esters With the desired cyanopyridyl boronic esters in hand we set out to synthesize biaryls 4b–d. Suzuki–Miyaura coupling of pyridylboronic acids or esters is notoriously difficult as these derivatives are prone to deborylation.10 Indeed, under standard Suzuki–Miyaura cross-coupling conditions we observed extensive deborylation, and the parent cyanopyridines were isolated as the main product with only traces of the desired biaryls. Therefore, a range of conditions and additives were tested in order to optimize the coupling. After extensive
Having established that the proposed synthetic route to azaphenanthridines was viable, we set out to prepare the three biaryl precursors (4b–d) needed for the remaining azaphenanthridines (3b–d). If the strategy shown in Scheme 2 was to be followed this would require the synthesis of the corresponding halocyanopyridines as these are not commercial available. Therefore, a different synthetic strategy was chosen. 2.1. Synthesis of cyanopyridylboronic esters We have reported a new synthetic procedure for the synthesis of arylboronic esters via in situ trapping of unstable lithio-intermediates.5 Following this method, benzonitrile was ortho-lithiated to give the corresponding cyanoarylboronic ester. Accordingly, 4b–d were envisaged to be prepared via a ortho-lithiation/cross-coupling
Scheme 6. Synthesis of biaryls via cross-coupling of cyanopyridylboronic esters.
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experimentation we found that addition of CuI11 in combination with CsF12 in an aprotic solvent was crucial for the success of the reaction. Under these conditions the desired biaryls 4b–d were isolated in 60–80% yield (see Scheme 6). 2.3. Synthesis of azaphenathridines Treatment of 4b and 4c with lithium morpholide gave the desired azaphenanthridines in excellent yields (see Scheme 7). Compound 4b gave 3b in 95% yield and 4c produced 3c in 97% yield.
Scheme 9. Addition of lithium morpholide to 4d.
promote the formation of intermediate 9. Running the experiment with 5 equiv LiCl did indeed improve the ratio between 3d and 7 to 94:6 (see Scheme 8, entry 3) and 3d was subsequently isolated in 88% yield.
3. Conclusion Scheme 7. Addition of lithium morpholide to 4b–c.
The reaction of 4d with lithium morpholide gave a 80:20 mixture of the desired product 3d and a compound identified as 7 (see Scheme 8, entry 1). The identity of 7 was unequivocally established by synthesizing 7 in two steps from 3-bromo-2-chloropyridine.13
A short, convergent and high yielding synthetic approach to four isomeric azaphenanthridines has been developed. We are currently exploring the scope of this approach to the synthesis of other heterocyclic phenanthridine systems.
4. Experimental 4.1. General All reactions involving air- and moisture sensitive reagents were performed under N2 using syringe-septum cap techniques. All glassware was flame dried under vacuum prior to use. THF was distilled from Na/Benzophenone. LiCl was flame dried under vacuum. All other chemicals were used as received from commercial suppliers.
Scheme 8. Addition of lithium morpholide to 4d.
Penney14 reported the synthesis of aminopyridines via the addition of lithium amides to cyanopyridines, and we speculate that 7 is formed in a similar fashion from the initial adduct 8 (see Scheme 9) where the lithium presumably is coordinated to the pyridine nitrogen. This intermediate can then proceed via two different pathways: (1) elimination of LiCN to produce 7, and (2) ‘decoordination’ of the lithium to the pyridine nitrogen leading to intermediate 9, which then produces 3d via intramolecular nucleophilic aromatic substitution of the fluorine. Penney reported that CsF promotes the formation of aminopyridines in the reaction, but we did not see any effect of CsF (see Scheme 8, entry 2). Encouraged by the effect of LiCl in the synthesis of 3a, we though that LiCl might also have an effect on the course of this reaction as excess LiCl should
4.1.1. 2-(2-Fluorophenyl)nicotinonitrile (4a). A 100 mL Schlenk-flask was charged with 2-chloro-nicotinonitrile (5a) (1.39 g, 10 mmol), 2-(2-fluorophenyl)-5,5-dimethyl[1,3,2]dioxaborinane5 (2.50 g, 12.0 mmol), K3PO4 (4.25 g, 20.0 mmol), Pd(PPh3)4 (0.58 g, 5 mol%), then evacuated and refilled with N2 three times before 1,4-dioxane (50 mL) was added. The reaction was stirred at 80 8C overnight, cooled to rt, evaporated on Celite and purified by FC to give 1.89 g 4a as off white crystals (95%). Mp (heptane/EtOAc) 74–76 8C. R f (heptane/EtOAc 3:1) 0.23. 1H NMR (300 MHz, CDCl3): d 8.86 (1H, dd, JZ5.0, 1.7 Hz), 8.08 (1H, dd, JZ7.9, 1.7 Hz), 7.58 (1H, td, JZ7.5, 1.8 Hz), 7.53–7.45 (m, 1H), 7.42 (1H, dd, JZ7.9, 5.0 Hz), 7.30 (1H, td, JZ7.5, 1.1 Hz), 7.21 (1H, d, JZ8.3 Hz). 13C NMR (75 MHz, CDCl3): d 159.6 (JC–FZ250 Hz), 157.1, 152.6, 140.7, 132.0 (JC–FZ8 Hz), 131.2 (JC–FZ3 Hz), 125.5 (JC–FZ14 Hz), 124.5 (JC–FZ4 Hz), 122.2, 116.4, 116.3 (JC–FZ22 Hz), 110.4. Anal. Calcd for C12H7FN2: C, 72.72; H, 3.56; N, 14.13. Found C, 72.58; H, 3.76; N, 14.35.
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4.2. General procedure for the synthesis of 5b–5d In a flame dried 250 mL Schlenk-flask 2,2,6,6-tetramethylpiperidine (5.06 mL, 30 mmol) was dissolved in dry THF (50 mL) under N2 and cooled to K30 8C before n-BuLi (30 mmol) was added via syringe over 2 min. The mixture was stirred at K30 8C for 5 min then cooled to K78 8C before B(OiPr)3 (8.08 mL, 35 mmol) was added via syringe over 2 min. The mixture was stirred at K78 8C for 5 min before the cyanopyridine (2.60 g, 25 mmol) dissolved in dry THF (50 mL) was added via syringe over 5 min. The reaction was left in the dry ice bath overnight slowly reaching rt. The reaction was quenched with glacial acetic acid (2.0 mL, 35 mmol) followed by addition of 2,2dimethyl-1,3-propandiol (3.91 g, 37.5 mmol). The mixture was stirred for 1 h at rt then poured into 10% KH2PO4(aq) (75 mL). The water phase was extracted with CH2Cl2 (4! 50 mL) and the combined organic phase was washed with water (4!15 mL). The organic phase was dried (MgSO4) and evaporated to give the crude product. 4.2.1. 3-(5,5-Dimethyl-[1,3,2]dioxaborinan-2-yl)isonicotinonitrile (5b). Following the general procedure, isonicotinonitrile yielded 4.32 g 5b as analytically pure dark-red crystals (80%). Recrystallization from heptane/ EtOAc gave white crystals. Mp 125–127 8C. 1H NMR (300 MHz, CDCl3): d 9.08 (1H, d, JZ0.8 Hz), 8.76 (1H, d, JZ5.1 Hz), 7.51 (1H, dd, JZ5.1, 0.9 Hz), 3.84 (4H, s), 1.06 (6H, s). 13C NMR (75 MHz, CDCl3): d 155.9, 151.5, 126.4, 124.5, 117.1, 72.5, 31.9, 21.9. Anal. Calcd for C11H13BN2O2: C, 61.15; H, 6.07; N, 12.97. Found C, 61.39; H, 5.86; N, 12.98. 4.2.2. 4-(5,5-Dimethyl-[1,3,2]dioxaborinan-2-yl)nicotinonitrile (5c). Following the general procedure, nicotinonitrile yielded 2.81 g 5c as analytically pure dark-brown crystals (52%). Recrystallization from heptane/EtOAc gave off white crystals. Mp 96–98 8C. 1H NMR (300 MHz, CDCl3): d 8.88 (1H, d, JZ0.7 Hz), 8.74 (1H, d, JZ 4.9 Hz), 7.77 (1H, dd, JZ4.9, 0.7 Hz), 3.84 (4H, s), 1.05 (6H, s). 13C NMR (75 MHz, CDCl3): d 152.8, 151.3, 128.2, 117.2, 113.1, 72.3, 31.7, 21.6. Anal. Calcd for C11H13BN2O2: C, 61.15; H, 6.07; N, 12.97. Found C, 60.85; H, 5.80; N, 13.26. 4.2.3. 3-(5,5-Dimethyl-[1,3,2]dioxaborinan-2-yl)picolinonitrile (5d). Following the general procedure, pyridine-2carbonitrile yielded 5.08 g 5d as analytically pure darkbrown crystals (94%). Recrystallization from heptane/ EtOAc gave white crystals. Mp 47–49 8C. 1H NMR (300 MHz, CDCl3): d 8.69 (1H, dd, JZ5.0, 1.7 Hz), 8.16 (1H, dd, JZ7.7, 1.7 Hz), 7.44 (1H, dd, JZ7.7, 5.0 Hz), 3.83 (4H, s), 1.05 (6H, s). 13C NMR (75 MHz, CDCl3): d 151.5, 142.7, 137.2, 125.6, 117.6, 72.2, 31.6, 21.5. Anal. Calcd for C11H13BN2O2: C, 61.15; H, 6.07; N, 12.97. Found C, 60.93; H, 6.15; N, 12.85. 4.3. General procedure for the synthesis of 4b–4d A Schlenk-flask was charged with the cyanopyridylboronic ester, 1-fluoro-2-iodobenzene (1.2 equiv), CsF (2 equiv), CuI (0.1 equiv), Pd(PPh3)4 (0.05 equiv), evacuated and refilled with N2 three times. 1,4-Dioxane (4 mL/mmol) was
added and the reaction was stirred vigorously under N2 at 60 8C for 5 h. The reaction was quenched with water (4 mL/ mmol) and the water phase was extracted with EtOAc (3! 20 mL), the organic phase was dried (MgSO4), evaporated on Celite and purified by FC. 4.3.1. 3-(2-Fluorophenyl)isonicotinonitrile (4b). Following the general procedure, 5b (1.94 g, 9.0 mmol) yielded 1.41 g 4b as white crystals (79%). Mp (heptane/ EtOAc) 50–52 8C. Rf (heptane/EtOAc 3:1) 0.25. 1H NMR (300 MHz, CDCl3): d 8.84 (1H, s), 8.79 (1H, d, JZ5.0 Hz), 7.65 (1H, dd, JZ5.0, 0.7 Hz), 7.56–7.48 (1H, m), 7.45 (1H, td, JZ7.5, 1.8 Hz), 7.32 (1H, td, JZ7.5, 1.2 Hz), 7.28–7.23 (1H, m). 13C NMR (75 MHz, CDCl3): d 159.5 (JC–FZ 249 Hz), 151.5 (JC–FZ2 Hz), 149.4, 133.2, 131.8 (JC–FZ 8 Hz), 131.1 (JC–FZ2 Hz), 125.7, 124.8 (JC–FZ4 Hz), 122.2 (JC–FZ15 Hz), 120.5, 116.4 (JC–FZ22 Hz), 115.7. Anal. Calcd for C12H7FN2: C, 72.72; H, 3.56; N, 14.13. Found C, 72.42; H, 3.58; N, 13.92. 4.3.2. 4-(2-Fluorophenyl)nicotinonitrile (4c). Following the general procedure, 5c (1.51 g, 7.0 mmol) yielded 832 mg 4c as white crystals (60%). Mp (heptane/EtOAc) 102–103 8C. Rf (heptane/EtOAc 3:1) 0.29. 1H NMR (300 MHz, CDCl3): d 8.96 (1H, s), 8.82 (1H, d, JZ 5.2 Hz), 7.55–7.45 (3H, m), 7.30 (1H, td, JZ7.6, 1.2 Hz), 7.24 (1H, td, JZ8.8, 1.2 Hz). 13C NMR (75 MHz, CDCl3): d 159.2 (JC–FZ251 Hz), 153.5, 152.6, 147.1, 132.3 (JC–FZ 8 Hz), 130.7 (JC–FZ2 Hz), 125.0 (JC–FZ2 Hz), 124.9 (JCFZ4 Hz), 123.3 (JC–FZ14 Hz), 116.6 (JC–FZ22 Hz), 116.1, 110.1. HRMS [MCH]C calcd for C12H7FN2: 199.0672, found: 199.0643. 4.3.3. 3-(2-Fluorophenyl)picolinonitrile (4d). Following the general procedure, 5d (4.75 g, 22.0 mmol) yielded 3.49 g 4d as white crystals (80%). Mp (heptane/EtOAc) 89– 90 8C. Rf (heptane/EtOAc 3:1) 0.24. 1H NMR (300 MHz, CDCl3): d 8.74 (1H, dd, JZ4.7, 1.2 Hz), 7.88 (1H, d, JZ 8.2 Hz), 7.60 (1H, dd, JZ7.6, 4.7 Hz), 7.55–7.43 (2H, m), 7.30 (1H, td, JZ7.6, 1.2 Hz), 7.21 (1H, d, JZ8.2 Hz). 13C NMR (75 MHz, CDCl3): d 159.3 (JC–FZ249 Hz), 149.9, 138.7 (JC–FZ2 Hz), 136.4, 133.2, 131.7 (JC–FZ8 Hz), 131.1(JC–FZ2 Hz), 126.5, 124.7 (JC–FZ4 Hz), 123.0 (JC–FZ15 Hz), 116.5, 116.3 (JC–FZ22 Hz). Anal. Calcd for C12H7FN2: C, 72.72; H, 3.56; N, 14.13. Found C, 72.54; H, 3.71; N, 14.00. 4.4. General procedure for the reaction of 4a–d with lithium morpholide In a flame dried Schlenk-flask under N2 at rt, morpholine (1.2 equiv) was dissolved in dry THF (2 mL/mmol). n-BuLi (1.2 equiv) was added and the mixture was stirred for 5 min before the biaryl (3a–d) dissolved in dry THF (1 mL/mmol) was added. The mixture was heated to reflux for 30 min. After cooling, the reaction was quenched with satd NH4Cl (aq) (20 mL) and extracted with CH2Cl2. The organic phase was dried (MgSO4), evaporated on Celite and purified by FC. 4.4.1. 6-Morpholino-10-azaphenanthridine (3a). Following the general procedure, with the addition of dry LiCl (5 equiv) 4a (396 mg, 2.0 mmol) yielded 413 mg 3a as
H. M. Hansen et al. / Tetrahedron 61 (2005) 9955–9960
white crystals (84%). Mp (heptane/EtOAc) 111–112 8C. Rf (heptane/EtOAc 2:1) 0.37. 1H NMR (300 MHz, CDCl3): d 9.08 (1H, dd, JZ4.1, 1.8 Hz), 8.96 (1H, dd, JZ8.2, 1.8 Hz), 8.43 (1H, dd, JZ8.2, 1.8 Hz), 7.94 (1H, d, JZ8.2 Hz), 7.73 (1H, td, JZ8.2, 1.2 Hz), 7.56 (1H, t, JZ7.6 Hz), 7.53 (1H, dd, JZ8.2, 4.1 Hz), 4.00 (4H, t, JZ4.7 Hz), 3.51 (4H, t, JZ 4.7 Hz). 13C NMR (75 MHz, CDCl3): d 159.2, 152.3, 151.0, 145.4, 134.1, 130.5, 127.9, 125.4, 123.8, 123.6, 121.6, 116.3, 67.1, 51.9. Anal. Calcd for C16H15N3O: C, 72.43; H, 5.70; N, 15.85. Found C, 72.44; H, 5.90; N, 15.86. 4.4.2. 6-Morpholino-9-azaphenanthridine (3b). Following the general procedure, 4b (991 mg, 5.0 mmol) yielded 1.27 g 3b as yellow crystals (95%). Mp (heptane/ EtOAc) 124–125 8C. Rf (heptane/EtOAc 3:1) 0.16. 1H NMR (300 MHz, CDCl3): d 9.97 (1H, s), 8.80 (1H, d, JZ5.9 Hz), 8.54 (1H, dd, JZ8.2, 1.8 Hz), 7.95 (1H, dd, JZ8.2, 1.2 Hz), 7.90 (1H, dd, JZ5.9, 1.2 Hz), 7.70 (1H, td, JZ7.0, 1.2 Hz), 7.57 (1H, td, JZ8.2, 1.8 Hz), 4.01 (4H, t, JZ4.7 Hz), 3.54 (4H, t, JZ4.7 Hz). 13C NMR (75 MHz, CDCl3): d 158.1, 147.5, 145.7, 143.9, 129.6, 129.0, 128.7, 125.77, 124.9, 121.2, 120.5, 118.4, 67.0, 51.4. Anal. Calcd for C16H15N3O: C, 72.43; H, 5.70; N, 15.85. Found C, 72.21; H, 5.66; N, 15.68. 4.4.3. 6-Morpholino-8-azaphenanthridine (3c). Following the general procedure, except the mixture was heated at reflux for 24 h, 4c (793 mg, 4.0 mmol) yielded 1.03 g 3c as yellow crystals (97%). Mp (heptane/EtOAc) 134–136 8C. Rf (heptane/EtOAc 3:1) 0.29. 1H NMR (300 MHz, CDCl3): d 9.48 (1H, s), 8.83 (1H, d, JZ 5.3 Hz), 8.36 (1H, d, JZ7.6, 1.2 Hz), 8.27 (1H, d, JZ 5.9 Hz,), 7.92 (1H, dd, JZ8.2, 1.2 Hz), 7.72 (1H, td, JZ7.0, 1.2 Hz), 7.51 (1H, td, JZ8.2, 1.2 Hz), 4.01 (4H, t, JZ 4.7 Hz), 3.57 (4H, t, JZ4.7 Hz). 13C NMR (75 MHz, CDCl3): d 159.0, 150.0, 148.2, 145.2, 140.4, 131.2, 128.7, 125.4, 122.6, 120.5, 116.0, 115.9, 67.0, 52.0. HRMS [MC H]C calcd for C16H15N3O: 266.1293, found: 266.1293. 4.4.4. 6-Morpholino-7-azaphenanthridine (3d). Following the general procedure, with the addition of dry LiCl (5 equiv) 4d (198 mg, 1.0 mmol) yielded 233 mg 3d as yellow crystals (88%). Mp (heptane/EtOAc) 104–105 8C. Rf (heptane/EtOAc 3:1) 0.20. 1H NMR (300 MHz, CDCl3): d 8.89 (1H, dd, JZ4.1, 1.8 Hz), 8.77 (1H, dd, JZ8.8, 1.8 Hz), 8.27 (1H, dd, JZ8.2, 1.2 Hz), 7.89 (1H, d, JZ8.2 Hz), 7.66–7.60 (2H, m), 7.43 (1H, td, JZ7.0, 1.2 Hz), 4.03 (8H, m). 13C NMR (75 MHz, CDCl3): d 157.2, 148.1, 143.5, 137.7, 130.9, 130.0, 129.6, 128.0, 124.6, 124.3, 121.8, 121.0, 67.2, 50.3. Anal. Calcd for C16H15N3O: C, 72.43; H, 5.70; N, 15.85. Found C, 72.15; H, 5.53; N, 15.75. 4.4.5. 2-(2-Morpholinophenyl)nicotinonitrile (6). A 5 mL vial for septum capping was charged with 4d (180 mg, 0.91 mmol) and morpholine (3 mL, 35 mmol), capped and heated in a Biotage Initiatore microwave system for 1 h at 225 8C. After cooling, the reaction was poured into satd NH4Cl (aq) (15 mL) and CH2Cl2 (15 mL) and the organic phase was washed with satd NH4Cl (aq) (2!15 mL) and the water phase was back extracted with CH2Cl2 (10 mL). The combined organic phases were dried (MgSO4), evaporated on Celite and purified by FC to give 186 mg 6 as a white solid (78%). Mp (Et2O) 133–134 8C. Rf (heptane/EtOAc
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3:1) 0.18. 1H NMR (300 MHz, CDCl3): d 8.86 (1H, dd, JZ 4.9, 1.7 Hz), 8.04 (1H, dd, JZ7.8, 1.7 Hz), 7.45 (td, 1H, JZ 7.7, 1.7 Hz), 7.39 (1H, dd, JZ7.2, 1.7 Hz), 7.36 (1H, dd, JZ7.7, 5.0 Hz), 7.25–7.15 (2H, m), 3.55 (4H, t, JZ4.4 Hz), 2.82 (4H, t, JZ4.4 Hz). 13C NMR (75 MHz, CDCl3): d 161.3, 152.6, 150.4, 140.1, 132.8, 130.9, 130.5, 123.9, 121.2, 119.4, 117.3, 110.9, 66.8, 51.9. Anal. Calcd for C16H15N3O: C, 72.43; H, 5.70; N, 15.84. Found C, 72.43; H, 5.77; N, 15.54. 4.4.6. 3-(2-Fluorophenyl)-2-morpholinopyridine (7). A 25 mL flask was charged with 3-bromo-2-chloropyridine (962 mg, 5.0 mmol), morpholine (871 mg, 10 mmol), K2CO3 (1.66 g, 12 mmol) and DMF (20 mL). The reaction was stirred overnight at 130 8C. After cooling to rt the reaction was poured into satd NH4Cl (aq) (50 mL) and Et2O (50 mL). The DMF-water phase was extracted with Et2O (3!20 mL) and the combined organic phase was dried (MgSO4), evaporated on Celite and purified by FC to give 840 mg 3-bromo-2-morpholinopyridine as white crystals (70%). Mp 94–95 8C. Rf (heptane/EtOAc 3:1) 0.42. 1H NMR (300 MHz, CDCl3): d 8.22 (1H, dd, JZ4.7, 1.6 Hz), 7.78 (1H, dd, JZ7.7, 1.6 Hz), 6.78 (1H, dd, JZ7.7, 4.7 Hz), 3.89–3.84 (4H, m), 3.36–3.31 (4H, m). 13C NMR (75 MHz, CDCl3): d 159.0, 146.3, 142.2, 118.6, 112.7, 66.8, 49.9. Anal. Calcd for C9H11BrN2O: C, 44.47; H, 4.56; N, 11.52. Found C, 44.47; H, 4.47; N, 11.44. A Schlenk-flask was charged with 3-bromo-2-morpholinopyridine (729 mg, 3.0 mmol), 2-(2-fluorophenyl)-5,5dimethyl-[1,3,2]dioxaborinane 5 (811 mg, 3.9 mmol), Pd(PPh3)4 (104 mg, 3 mol%) and evacuated and refilled with N2 three times. Toluene (15 mL), EtOH (3 mL), 2 M K2CO3 (aq) (3 mL) was added and the reaction was stirred at 100 8C for 3 h. After cooling the mixture was poured into water (30 mL) and the water phase was extracted with CH2Cl2 (3!20 mL), dried (MgSO4), evaporated on Celite and purified on FC to give 642 mg 7 as a colourless oil (83%). Rf (heptane/EtOAc 3:1) 0.27. 1H NMR (300 MHz, CDCl3): d 8.28 (1H, dd, JZ4.8, 1.8 Hz), 7.54–7.47 (2H, m), 7.38–7.29 (1H, m), 7.20 (1H, m), 7.16 (1H, m), 6.94 (1H, dd, JZ7.5, 4.9 Hz), 3.59 (4H, t, JZ4.7 Hz), 3.13 (4H, t, JZ 4.7 Hz). 13C NMR (75 MHz, CDCl3): d 159.5, 159.2 (JC–FZ248 Hz), 147.0, 140.7, 130.7 (JC–FZ3 Hz), 129.6 (JC–FZ8 Hz), 127.1 (JC–FZ15 Hz), 124.5 (JC–FZ4 Hz), 121.4, 116.7, 116.4 (JC–FZ22 Hz), 66.9, 49.4. Anal. Calcd for C15H15FN2O: C, 69.75; H, 5.85; N, 10.85. Found C, 69.38; H, 5.84; N, 10.23.
References and notes 1. Lyse´n, M.; Kristensen, J. L.; Vedsø, P.; Begtrup, M. Org. Lett. 2002, 257. 2. (a) Roseman, K. A.; Gould, M. M.; Linfield, W. M.; Edwards, B. E. J. Med. Chem. 1970, 13, 230. (b) Loy, M.; Joullie, M. M. J. Med. Chem. 1973, 16, 549. (c) Yapi, A. D.; Mustofa, M.; Valentin, A.; Chavignon, O.; Teulade, J. C.; Mallie, M.; Chapat, J. P.; Blache, Y. Chem. Pharm. Bull. 2000, 48, 1886. (d) Hinschberger, A.; Butt, S.; Lelong, V.; Boulouard, M.; Dumuis, A.; Dauphin, F.; Bureau, R.; Pfeiffer, B.; Renard, P.;
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4.
5.
6. 7.
8. 9.
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Rault, S. J. Med. Chem. 2003, 46, 138. (e) Molinski, T. F. Chem. Rev. 1993, 93, 1825. (f) Marshall, K. M.; Barrows, L. R. Nat. Prod. Rep. 2004, 21, 731. For an extensive list of references to the synthesis of phenanthridines in general see: Patra, P. K.; Suresh, J. R.; Ila, H.; Junjappa, H. Tetrahedron 1998, 54, 10167. (a) Miyaura, N.; Yanagi, T.; Suzuki, A. Synth. Commun. 1981, 11, 513. (b) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457. (a) Kristensen, J. L.; Lyse´n, M.; Vedsø, P.; Begtrup, M. Org. Lett. 2001, 1435. (b) Kristensen, J. L.; Lyse´n, M.; Vedsø, P.; Begtrup, M. Org. Synth. 2005, 81, 134. When 4a was heated in neat morpholine at 225 8C for 1 h, 6 was produced in 78% isolated yield, see Section 4 for details. (a) Meyers, A. I.; Williams, B. E. Tetrahedron Lett. 1978, 3, 223. (b) For a review, see: Reuman, M.; Meyers, A. I. Tetrahedron 1985, 41, 837. DMPUZN,N 0 -dimethyl-N,N 0 -propyleneurea, see: Seebach, D.; Mukhopadhyay, T. Helv. Chim. Acta 1982, 65, 385. At that time there was only a single report in the in the literature describing an unselective ortho-lithiation of 3-cyanopyridine: Pletnev, A. A.; Tian, Q.; Larock, R. C. J. Org. Chem. 2002, 67, 9276. Recently a more general study
10. 11.
12.
13.
appeared describing the lithiation of cyanopyridines, see: Cailly, T.; Fabis, F.; Lemaıˆtre, S.; Bouillon, A.; Rault, S. Tetrahedron Lett. 2005, 46, 135. For a recent review of heterocyclic boronic acids see: Tyrrell, E.; Brookes, P. Synthesis 2004, 4, 469. Recently the addition of CuI was reported to be crucial in the coupling of other pyridylboronic derivatives: (a) Hodgson, P. B.; Salingue, F. H. Tetrahedron Lett. 2004, 45, 685. (b) Gros, P.; Doudouh, A.; Fort, Y. Tetrahedron Lett. 2004, 45, 6239. Fluoride activation in Suzuki–Miyaura couplings, see: Wright, S. W.; Hageman, D. L.; McClure, L. D. J. Org. Chem. 1994, 59, 6095. Alternative synthesis of 7 from 3-bromo-2-chloropyridine, see Section 4 for details.
14. Penney, J. M. Tetrahedron Lett. 2004, 45, 2667.
Synthesis of azaphenanthridines via anionic ring closure Henriette M. Hansen, Morten Lyse´n, Mikael Begtrup and Jesper L. Kristensen* Department of Medicinal Chemistry, Danish University of Pharmaceutical Sciences, Universitetsparken 2, 2100 Copenhagen, Denmark Received 13 June 2005; revised 25 July 2005; accepted 11 August 2005 Available online 29 August 2005
Abstract—A new and convergent synthesis of azaphenanthridines via an anionic ring closure is reported. Ortho-lithiation/in situ borylation of cyanopyridines produces the corresponding cyanopyridylboronic esters, which undergo a Suzuki–Miyaura cross-coupling to give the key intermediates. Addition of lithium morpholide produces the azaphenanthridines. q 2005 Elsevier Ltd. All rights reserved.
1. Introduction We have previously reported a convergent synthetic protocol for the synthesis of 6-substituted phenanthridines (2) from biaryl 1 (see Scheme 1).1 The reaction proceeds via attack of a lithiated species on the cyanogroup in 1 followed by intramolecular nucleophilic aromatic substitution of the fluorine.
Substituted azaphenanthridines have a broad spectrum of biological activities, including antimalarial2a–c and analgesic activity.2d Furthermore, the 8-azaphenanthridine ring system in 3c is the backbone of the pyridoacridine alkaloids,2e which exhibit anti-bacterial, anti-viral, anticancer activity,2f thus, a short and convergent approach to these ring systems would be highly desirable. Numerous different approaches to azaphenanthridines have been reported in the litterature,3 but all lack the flexibility to produce all the targeted isomers in this study.
2. Results and discussion
Scheme 1. Synthesis of 6-substituted phenanthridines via anionic ring closure.1
The retrosynthetic strategy is exemplified for the synthesis of 3a from biaryl 4a, which in turn should be accessible from commercially available 2-chloronicotinonitrile (5a) via a Suzuki–Miyaura cross-coupling4 (see Scheme 2).
We were interested in expanding the scope of our approach to the synthesis of heterocyclic phenanthridine derivatives, and set out to investigate whether it would be possible to synthesize the four isomeric 6-morpholinoaza-phenanthridines 3a–d shown in Figure 1 using this strategy. Scheme 2. Retrosynthetic analysis of 3a.
Indeed, coupling of 5a with the depicted 2-fluorophenylboronic ester5 gave biaryl 4a in 95% isolated yield (see Scheme 3). Figure 1. Targeted azaphenathridines. RZmorpholine. Keywords: Pyridines; Lithiation; Anionic ring closure. * Corresponding author. Tel.: C45 35306487; fax: C45 35306040; e-mail: [email protected] 0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.tet.2005.08.051
With the desired biaryl in hand we were ready to test the proposed ring closure. Treating 4a with lithium morpholide at reflux yielded a 37:63 mixture of the desired azaphenanthridine 3a together with 6 resulting from nucleophilic
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Scheme 3. Synthesis of 4a.
sequence of cyanopyridines.9 Submitting 2-, 3- and 4-cyanopyridine to our standard conditions for in situ trapping with LiTMP/B(OiPr)3 produced the desired cyanopyridylboronic esters 5b–d in 52–94% isolated yield (see Scheme 5). In all cases, GC–MS of the crude material showed full conversion to the desired cyanopyridylboronic esters.
Scheme 4. Addition of lithium morpholide to 4a.
aromatic substitution of fluorine by lithium morpholide6 (see Scheme 4, entry 1). We speculated that coordination of lithium morpholide to the pyridine nitrogen was a prerequisite for the direct nucleophilic substitution as seen in the work by Meyers and co-workers on nucleophilic aromatic substitution on 2-fluoro-aryloxazolines.7 If this coordination could be impeded, perhaps the ratio between 3a and 6 would increase. Repeating the experiment with 2 equiv of DMPU8 did improve the ratio (see Scheme 4, entry 2) and 5 equiv of DMPU accentuated the effect even more to give a 83:17 mixture of 3a and 6 (see Scheme 4, entry 3). Increasing the amount of DMPU did not influence the ratio further and let to a decrease in conversion. LiCl was tried as additive in an attempt to pre-complex the pyridine nitrogen, preventing lithium morpholide from coordinating, and the result was remarkable (see Scheme 4, entry 4). With 5 equiv of LiCl the desired product was the only detectable species, and 3a was obtained in 84% isolated yield.
Scheme 5. Synthesis of cyanopyridylboronic esters 5b–d.
2.2. Cross-coupling of cyanopyridylboronic esters With the desired cyanopyridyl boronic esters in hand we set out to synthesize biaryls 4b–d. Suzuki–Miyaura coupling of pyridylboronic acids or esters is notoriously difficult as these derivatives are prone to deborylation.10 Indeed, under standard Suzuki–Miyaura cross-coupling conditions we observed extensive deborylation, and the parent cyanopyridines were isolated as the main product with only traces of the desired biaryls. Therefore, a range of conditions and additives were tested in order to optimize the coupling. After extensive
Having established that the proposed synthetic route to azaphenanthridines was viable, we set out to prepare the three biaryl precursors (4b–d) needed for the remaining azaphenanthridines (3b–d). If the strategy shown in Scheme 2 was to be followed this would require the synthesis of the corresponding halocyanopyridines as these are not commercial available. Therefore, a different synthetic strategy was chosen. 2.1. Synthesis of cyanopyridylboronic esters We have reported a new synthetic procedure for the synthesis of arylboronic esters via in situ trapping of unstable lithio-intermediates.5 Following this method, benzonitrile was ortho-lithiated to give the corresponding cyanoarylboronic ester. Accordingly, 4b–d were envisaged to be prepared via a ortho-lithiation/cross-coupling
Scheme 6. Synthesis of biaryls via cross-coupling of cyanopyridylboronic esters.
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experimentation we found that addition of CuI11 in combination with CsF12 in an aprotic solvent was crucial for the success of the reaction. Under these conditions the desired biaryls 4b–d were isolated in 60–80% yield (see Scheme 6). 2.3. Synthesis of azaphenathridines Treatment of 4b and 4c with lithium morpholide gave the desired azaphenanthridines in excellent yields (see Scheme 7). Compound 4b gave 3b in 95% yield and 4c produced 3c in 97% yield.
Scheme 9. Addition of lithium morpholide to 4d.
promote the formation of intermediate 9. Running the experiment with 5 equiv LiCl did indeed improve the ratio between 3d and 7 to 94:6 (see Scheme 8, entry 3) and 3d was subsequently isolated in 88% yield.
3. Conclusion Scheme 7. Addition of lithium morpholide to 4b–c.
The reaction of 4d with lithium morpholide gave a 80:20 mixture of the desired product 3d and a compound identified as 7 (see Scheme 8, entry 1). The identity of 7 was unequivocally established by synthesizing 7 in two steps from 3-bromo-2-chloropyridine.13
A short, convergent and high yielding synthetic approach to four isomeric azaphenanthridines has been developed. We are currently exploring the scope of this approach to the synthesis of other heterocyclic phenanthridine systems.
4. Experimental 4.1. General All reactions involving air- and moisture sensitive reagents were performed under N2 using syringe-septum cap techniques. All glassware was flame dried under vacuum prior to use. THF was distilled from Na/Benzophenone. LiCl was flame dried under vacuum. All other chemicals were used as received from commercial suppliers.
Scheme 8. Addition of lithium morpholide to 4d.
Penney14 reported the synthesis of aminopyridines via the addition of lithium amides to cyanopyridines, and we speculate that 7 is formed in a similar fashion from the initial adduct 8 (see Scheme 9) where the lithium presumably is coordinated to the pyridine nitrogen. This intermediate can then proceed via two different pathways: (1) elimination of LiCN to produce 7, and (2) ‘decoordination’ of the lithium to the pyridine nitrogen leading to intermediate 9, which then produces 3d via intramolecular nucleophilic aromatic substitution of the fluorine. Penney reported that CsF promotes the formation of aminopyridines in the reaction, but we did not see any effect of CsF (see Scheme 8, entry 2). Encouraged by the effect of LiCl in the synthesis of 3a, we though that LiCl might also have an effect on the course of this reaction as excess LiCl should
4.1.1. 2-(2-Fluorophenyl)nicotinonitrile (4a). A 100 mL Schlenk-flask was charged with 2-chloro-nicotinonitrile (5a) (1.39 g, 10 mmol), 2-(2-fluorophenyl)-5,5-dimethyl[1,3,2]dioxaborinane5 (2.50 g, 12.0 mmol), K3PO4 (4.25 g, 20.0 mmol), Pd(PPh3)4 (0.58 g, 5 mol%), then evacuated and refilled with N2 three times before 1,4-dioxane (50 mL) was added. The reaction was stirred at 80 8C overnight, cooled to rt, evaporated on Celite and purified by FC to give 1.89 g 4a as off white crystals (95%). Mp (heptane/EtOAc) 74–76 8C. R f (heptane/EtOAc 3:1) 0.23. 1H NMR (300 MHz, CDCl3): d 8.86 (1H, dd, JZ5.0, 1.7 Hz), 8.08 (1H, dd, JZ7.9, 1.7 Hz), 7.58 (1H, td, JZ7.5, 1.8 Hz), 7.53–7.45 (m, 1H), 7.42 (1H, dd, JZ7.9, 5.0 Hz), 7.30 (1H, td, JZ7.5, 1.1 Hz), 7.21 (1H, d, JZ8.3 Hz). 13C NMR (75 MHz, CDCl3): d 159.6 (JC–FZ250 Hz), 157.1, 152.6, 140.7, 132.0 (JC–FZ8 Hz), 131.2 (JC–FZ3 Hz), 125.5 (JC–FZ14 Hz), 124.5 (JC–FZ4 Hz), 122.2, 116.4, 116.3 (JC–FZ22 Hz), 110.4. Anal. Calcd for C12H7FN2: C, 72.72; H, 3.56; N, 14.13. Found C, 72.58; H, 3.76; N, 14.35.
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4.2. General procedure for the synthesis of 5b–5d In a flame dried 250 mL Schlenk-flask 2,2,6,6-tetramethylpiperidine (5.06 mL, 30 mmol) was dissolved in dry THF (50 mL) under N2 and cooled to K30 8C before n-BuLi (30 mmol) was added via syringe over 2 min. The mixture was stirred at K30 8C for 5 min then cooled to K78 8C before B(OiPr)3 (8.08 mL, 35 mmol) was added via syringe over 2 min. The mixture was stirred at K78 8C for 5 min before the cyanopyridine (2.60 g, 25 mmol) dissolved in dry THF (50 mL) was added via syringe over 5 min. The reaction was left in the dry ice bath overnight slowly reaching rt. The reaction was quenched with glacial acetic acid (2.0 mL, 35 mmol) followed by addition of 2,2dimethyl-1,3-propandiol (3.91 g, 37.5 mmol). The mixture was stirred for 1 h at rt then poured into 10% KH2PO4(aq) (75 mL). The water phase was extracted with CH2Cl2 (4! 50 mL) and the combined organic phase was washed with water (4!15 mL). The organic phase was dried (MgSO4) and evaporated to give the crude product. 4.2.1. 3-(5,5-Dimethyl-[1,3,2]dioxaborinan-2-yl)isonicotinonitrile (5b). Following the general procedure, isonicotinonitrile yielded 4.32 g 5b as analytically pure dark-red crystals (80%). Recrystallization from heptane/ EtOAc gave white crystals. Mp 125–127 8C. 1H NMR (300 MHz, CDCl3): d 9.08 (1H, d, JZ0.8 Hz), 8.76 (1H, d, JZ5.1 Hz), 7.51 (1H, dd, JZ5.1, 0.9 Hz), 3.84 (4H, s), 1.06 (6H, s). 13C NMR (75 MHz, CDCl3): d 155.9, 151.5, 126.4, 124.5, 117.1, 72.5, 31.9, 21.9. Anal. Calcd for C11H13BN2O2: C, 61.15; H, 6.07; N, 12.97. Found C, 61.39; H, 5.86; N, 12.98. 4.2.2. 4-(5,5-Dimethyl-[1,3,2]dioxaborinan-2-yl)nicotinonitrile (5c). Following the general procedure, nicotinonitrile yielded 2.81 g 5c as analytically pure dark-brown crystals (52%). Recrystallization from heptane/EtOAc gave off white crystals. Mp 96–98 8C. 1H NMR (300 MHz, CDCl3): d 8.88 (1H, d, JZ0.7 Hz), 8.74 (1H, d, JZ 4.9 Hz), 7.77 (1H, dd, JZ4.9, 0.7 Hz), 3.84 (4H, s), 1.05 (6H, s). 13C NMR (75 MHz, CDCl3): d 152.8, 151.3, 128.2, 117.2, 113.1, 72.3, 31.7, 21.6. Anal. Calcd for C11H13BN2O2: C, 61.15; H, 6.07; N, 12.97. Found C, 60.85; H, 5.80; N, 13.26. 4.2.3. 3-(5,5-Dimethyl-[1,3,2]dioxaborinan-2-yl)picolinonitrile (5d). Following the general procedure, pyridine-2carbonitrile yielded 5.08 g 5d as analytically pure darkbrown crystals (94%). Recrystallization from heptane/ EtOAc gave white crystals. Mp 47–49 8C. 1H NMR (300 MHz, CDCl3): d 8.69 (1H, dd, JZ5.0, 1.7 Hz), 8.16 (1H, dd, JZ7.7, 1.7 Hz), 7.44 (1H, dd, JZ7.7, 5.0 Hz), 3.83 (4H, s), 1.05 (6H, s). 13C NMR (75 MHz, CDCl3): d 151.5, 142.7, 137.2, 125.6, 117.6, 72.2, 31.6, 21.5. Anal. Calcd for C11H13BN2O2: C, 61.15; H, 6.07; N, 12.97. Found C, 60.93; H, 6.15; N, 12.85. 4.3. General procedure for the synthesis of 4b–4d A Schlenk-flask was charged with the cyanopyridylboronic ester, 1-fluoro-2-iodobenzene (1.2 equiv), CsF (2 equiv), CuI (0.1 equiv), Pd(PPh3)4 (0.05 equiv), evacuated and refilled with N2 three times. 1,4-Dioxane (4 mL/mmol) was
added and the reaction was stirred vigorously under N2 at 60 8C for 5 h. The reaction was quenched with water (4 mL/ mmol) and the water phase was extracted with EtOAc (3! 20 mL), the organic phase was dried (MgSO4), evaporated on Celite and purified by FC. 4.3.1. 3-(2-Fluorophenyl)isonicotinonitrile (4b). Following the general procedure, 5b (1.94 g, 9.0 mmol) yielded 1.41 g 4b as white crystals (79%). Mp (heptane/ EtOAc) 50–52 8C. Rf (heptane/EtOAc 3:1) 0.25. 1H NMR (300 MHz, CDCl3): d 8.84 (1H, s), 8.79 (1H, d, JZ5.0 Hz), 7.65 (1H, dd, JZ5.0, 0.7 Hz), 7.56–7.48 (1H, m), 7.45 (1H, td, JZ7.5, 1.8 Hz), 7.32 (1H, td, JZ7.5, 1.2 Hz), 7.28–7.23 (1H, m). 13C NMR (75 MHz, CDCl3): d 159.5 (JC–FZ 249 Hz), 151.5 (JC–FZ2 Hz), 149.4, 133.2, 131.8 (JC–FZ 8 Hz), 131.1 (JC–FZ2 Hz), 125.7, 124.8 (JC–FZ4 Hz), 122.2 (JC–FZ15 Hz), 120.5, 116.4 (JC–FZ22 Hz), 115.7. Anal. Calcd for C12H7FN2: C, 72.72; H, 3.56; N, 14.13. Found C, 72.42; H, 3.58; N, 13.92. 4.3.2. 4-(2-Fluorophenyl)nicotinonitrile (4c). Following the general procedure, 5c (1.51 g, 7.0 mmol) yielded 832 mg 4c as white crystals (60%). Mp (heptane/EtOAc) 102–103 8C. Rf (heptane/EtOAc 3:1) 0.29. 1H NMR (300 MHz, CDCl3): d 8.96 (1H, s), 8.82 (1H, d, JZ 5.2 Hz), 7.55–7.45 (3H, m), 7.30 (1H, td, JZ7.6, 1.2 Hz), 7.24 (1H, td, JZ8.8, 1.2 Hz). 13C NMR (75 MHz, CDCl3): d 159.2 (JC–FZ251 Hz), 153.5, 152.6, 147.1, 132.3 (JC–FZ 8 Hz), 130.7 (JC–FZ2 Hz), 125.0 (JC–FZ2 Hz), 124.9 (JCFZ4 Hz), 123.3 (JC–FZ14 Hz), 116.6 (JC–FZ22 Hz), 116.1, 110.1. HRMS [MCH]C calcd for C12H7FN2: 199.0672, found: 199.0643. 4.3.3. 3-(2-Fluorophenyl)picolinonitrile (4d). Following the general procedure, 5d (4.75 g, 22.0 mmol) yielded 3.49 g 4d as white crystals (80%). Mp (heptane/EtOAc) 89– 90 8C. Rf (heptane/EtOAc 3:1) 0.24. 1H NMR (300 MHz, CDCl3): d 8.74 (1H, dd, JZ4.7, 1.2 Hz), 7.88 (1H, d, JZ 8.2 Hz), 7.60 (1H, dd, JZ7.6, 4.7 Hz), 7.55–7.43 (2H, m), 7.30 (1H, td, JZ7.6, 1.2 Hz), 7.21 (1H, d, JZ8.2 Hz). 13C NMR (75 MHz, CDCl3): d 159.3 (JC–FZ249 Hz), 149.9, 138.7 (JC–FZ2 Hz), 136.4, 133.2, 131.7 (JC–FZ8 Hz), 131.1(JC–FZ2 Hz), 126.5, 124.7 (JC–FZ4 Hz), 123.0 (JC–FZ15 Hz), 116.5, 116.3 (JC–FZ22 Hz). Anal. Calcd for C12H7FN2: C, 72.72; H, 3.56; N, 14.13. Found C, 72.54; H, 3.71; N, 14.00. 4.4. General procedure for the reaction of 4a–d with lithium morpholide In a flame dried Schlenk-flask under N2 at rt, morpholine (1.2 equiv) was dissolved in dry THF (2 mL/mmol). n-BuLi (1.2 equiv) was added and the mixture was stirred for 5 min before the biaryl (3a–d) dissolved in dry THF (1 mL/mmol) was added. The mixture was heated to reflux for 30 min. After cooling, the reaction was quenched with satd NH4Cl (aq) (20 mL) and extracted with CH2Cl2. The organic phase was dried (MgSO4), evaporated on Celite and purified by FC. 4.4.1. 6-Morpholino-10-azaphenanthridine (3a). Following the general procedure, with the addition of dry LiCl (5 equiv) 4a (396 mg, 2.0 mmol) yielded 413 mg 3a as
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white crystals (84%). Mp (heptane/EtOAc) 111–112 8C. Rf (heptane/EtOAc 2:1) 0.37. 1H NMR (300 MHz, CDCl3): d 9.08 (1H, dd, JZ4.1, 1.8 Hz), 8.96 (1H, dd, JZ8.2, 1.8 Hz), 8.43 (1H, dd, JZ8.2, 1.8 Hz), 7.94 (1H, d, JZ8.2 Hz), 7.73 (1H, td, JZ8.2, 1.2 Hz), 7.56 (1H, t, JZ7.6 Hz), 7.53 (1H, dd, JZ8.2, 4.1 Hz), 4.00 (4H, t, JZ4.7 Hz), 3.51 (4H, t, JZ 4.7 Hz). 13C NMR (75 MHz, CDCl3): d 159.2, 152.3, 151.0, 145.4, 134.1, 130.5, 127.9, 125.4, 123.8, 123.6, 121.6, 116.3, 67.1, 51.9. Anal. Calcd for C16H15N3O: C, 72.43; H, 5.70; N, 15.85. Found C, 72.44; H, 5.90; N, 15.86. 4.4.2. 6-Morpholino-9-azaphenanthridine (3b). Following the general procedure, 4b (991 mg, 5.0 mmol) yielded 1.27 g 3b as yellow crystals (95%). Mp (heptane/ EtOAc) 124–125 8C. Rf (heptane/EtOAc 3:1) 0.16. 1H NMR (300 MHz, CDCl3): d 9.97 (1H, s), 8.80 (1H, d, JZ5.9 Hz), 8.54 (1H, dd, JZ8.2, 1.8 Hz), 7.95 (1H, dd, JZ8.2, 1.2 Hz), 7.90 (1H, dd, JZ5.9, 1.2 Hz), 7.70 (1H, td, JZ7.0, 1.2 Hz), 7.57 (1H, td, JZ8.2, 1.8 Hz), 4.01 (4H, t, JZ4.7 Hz), 3.54 (4H, t, JZ4.7 Hz). 13C NMR (75 MHz, CDCl3): d 158.1, 147.5, 145.7, 143.9, 129.6, 129.0, 128.7, 125.77, 124.9, 121.2, 120.5, 118.4, 67.0, 51.4. Anal. Calcd for C16H15N3O: C, 72.43; H, 5.70; N, 15.85. Found C, 72.21; H, 5.66; N, 15.68. 4.4.3. 6-Morpholino-8-azaphenanthridine (3c). Following the general procedure, except the mixture was heated at reflux for 24 h, 4c (793 mg, 4.0 mmol) yielded 1.03 g 3c as yellow crystals (97%). Mp (heptane/EtOAc) 134–136 8C. Rf (heptane/EtOAc 3:1) 0.29. 1H NMR (300 MHz, CDCl3): d 9.48 (1H, s), 8.83 (1H, d, JZ 5.3 Hz), 8.36 (1H, d, JZ7.6, 1.2 Hz), 8.27 (1H, d, JZ 5.9 Hz,), 7.92 (1H, dd, JZ8.2, 1.2 Hz), 7.72 (1H, td, JZ7.0, 1.2 Hz), 7.51 (1H, td, JZ8.2, 1.2 Hz), 4.01 (4H, t, JZ 4.7 Hz), 3.57 (4H, t, JZ4.7 Hz). 13C NMR (75 MHz, CDCl3): d 159.0, 150.0, 148.2, 145.2, 140.4, 131.2, 128.7, 125.4, 122.6, 120.5, 116.0, 115.9, 67.0, 52.0. HRMS [MC H]C calcd for C16H15N3O: 266.1293, found: 266.1293. 4.4.4. 6-Morpholino-7-azaphenanthridine (3d). Following the general procedure, with the addition of dry LiCl (5 equiv) 4d (198 mg, 1.0 mmol) yielded 233 mg 3d as yellow crystals (88%). Mp (heptane/EtOAc) 104–105 8C. Rf (heptane/EtOAc 3:1) 0.20. 1H NMR (300 MHz, CDCl3): d 8.89 (1H, dd, JZ4.1, 1.8 Hz), 8.77 (1H, dd, JZ8.8, 1.8 Hz), 8.27 (1H, dd, JZ8.2, 1.2 Hz), 7.89 (1H, d, JZ8.2 Hz), 7.66–7.60 (2H, m), 7.43 (1H, td, JZ7.0, 1.2 Hz), 4.03 (8H, m). 13C NMR (75 MHz, CDCl3): d 157.2, 148.1, 143.5, 137.7, 130.9, 130.0, 129.6, 128.0, 124.6, 124.3, 121.8, 121.0, 67.2, 50.3. Anal. Calcd for C16H15N3O: C, 72.43; H, 5.70; N, 15.85. Found C, 72.15; H, 5.53; N, 15.75. 4.4.5. 2-(2-Morpholinophenyl)nicotinonitrile (6). A 5 mL vial for septum capping was charged with 4d (180 mg, 0.91 mmol) and morpholine (3 mL, 35 mmol), capped and heated in a Biotage Initiatore microwave system for 1 h at 225 8C. After cooling, the reaction was poured into satd NH4Cl (aq) (15 mL) and CH2Cl2 (15 mL) and the organic phase was washed with satd NH4Cl (aq) (2!15 mL) and the water phase was back extracted with CH2Cl2 (10 mL). The combined organic phases were dried (MgSO4), evaporated on Celite and purified by FC to give 186 mg 6 as a white solid (78%). Mp (Et2O) 133–134 8C. Rf (heptane/EtOAc
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3:1) 0.18. 1H NMR (300 MHz, CDCl3): d 8.86 (1H, dd, JZ 4.9, 1.7 Hz), 8.04 (1H, dd, JZ7.8, 1.7 Hz), 7.45 (td, 1H, JZ 7.7, 1.7 Hz), 7.39 (1H, dd, JZ7.2, 1.7 Hz), 7.36 (1H, dd, JZ7.7, 5.0 Hz), 7.25–7.15 (2H, m), 3.55 (4H, t, JZ4.4 Hz), 2.82 (4H, t, JZ4.4 Hz). 13C NMR (75 MHz, CDCl3): d 161.3, 152.6, 150.4, 140.1, 132.8, 130.9, 130.5, 123.9, 121.2, 119.4, 117.3, 110.9, 66.8, 51.9. Anal. Calcd for C16H15N3O: C, 72.43; H, 5.70; N, 15.84. Found C, 72.43; H, 5.77; N, 15.54. 4.4.6. 3-(2-Fluorophenyl)-2-morpholinopyridine (7). A 25 mL flask was charged with 3-bromo-2-chloropyridine (962 mg, 5.0 mmol), morpholine (871 mg, 10 mmol), K2CO3 (1.66 g, 12 mmol) and DMF (20 mL). The reaction was stirred overnight at 130 8C. After cooling to rt the reaction was poured into satd NH4Cl (aq) (50 mL) and Et2O (50 mL). The DMF-water phase was extracted with Et2O (3!20 mL) and the combined organic phase was dried (MgSO4), evaporated on Celite and purified by FC to give 840 mg 3-bromo-2-morpholinopyridine as white crystals (70%). Mp 94–95 8C. Rf (heptane/EtOAc 3:1) 0.42. 1H NMR (300 MHz, CDCl3): d 8.22 (1H, dd, JZ4.7, 1.6 Hz), 7.78 (1H, dd, JZ7.7, 1.6 Hz), 6.78 (1H, dd, JZ7.7, 4.7 Hz), 3.89–3.84 (4H, m), 3.36–3.31 (4H, m). 13C NMR (75 MHz, CDCl3): d 159.0, 146.3, 142.2, 118.6, 112.7, 66.8, 49.9. Anal. Calcd for C9H11BrN2O: C, 44.47; H, 4.56; N, 11.52. Found C, 44.47; H, 4.47; N, 11.44. A Schlenk-flask was charged with 3-bromo-2-morpholinopyridine (729 mg, 3.0 mmol), 2-(2-fluorophenyl)-5,5dimethyl-[1,3,2]dioxaborinane 5 (811 mg, 3.9 mmol), Pd(PPh3)4 (104 mg, 3 mol%) and evacuated and refilled with N2 three times. Toluene (15 mL), EtOH (3 mL), 2 M K2CO3 (aq) (3 mL) was added and the reaction was stirred at 100 8C for 3 h. After cooling the mixture was poured into water (30 mL) and the water phase was extracted with CH2Cl2 (3!20 mL), dried (MgSO4), evaporated on Celite and purified on FC to give 642 mg 7 as a colourless oil (83%). Rf (heptane/EtOAc 3:1) 0.27. 1H NMR (300 MHz, CDCl3): d 8.28 (1H, dd, JZ4.8, 1.8 Hz), 7.54–7.47 (2H, m), 7.38–7.29 (1H, m), 7.20 (1H, m), 7.16 (1H, m), 6.94 (1H, dd, JZ7.5, 4.9 Hz), 3.59 (4H, t, JZ4.7 Hz), 3.13 (4H, t, JZ 4.7 Hz). 13C NMR (75 MHz, CDCl3): d 159.5, 159.2 (JC–FZ248 Hz), 147.0, 140.7, 130.7 (JC–FZ3 Hz), 129.6 (JC–FZ8 Hz), 127.1 (JC–FZ15 Hz), 124.5 (JC–FZ4 Hz), 121.4, 116.7, 116.4 (JC–FZ22 Hz), 66.9, 49.4. Anal. Calcd for C15H15FN2O: C, 69.75; H, 5.85; N, 10.85. Found C, 69.38; H, 5.84; N, 10.23.
References and notes 1. Lyse´n, M.; Kristensen, J. L.; Vedsø, P.; Begtrup, M. Org. Lett. 2002, 257. 2. (a) Roseman, K. A.; Gould, M. M.; Linfield, W. M.; Edwards, B. E. J. Med. Chem. 1970, 13, 230. (b) Loy, M.; Joullie, M. M. J. Med. Chem. 1973, 16, 549. (c) Yapi, A. D.; Mustofa, M.; Valentin, A.; Chavignon, O.; Teulade, J. C.; Mallie, M.; Chapat, J. P.; Blache, Y. Chem. Pharm. Bull. 2000, 48, 1886. (d) Hinschberger, A.; Butt, S.; Lelong, V.; Boulouard, M.; Dumuis, A.; Dauphin, F.; Bureau, R.; Pfeiffer, B.; Renard, P.;
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4.
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6. 7.
8. 9.
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Rault, S. J. Med. Chem. 2003, 46, 138. (e) Molinski, T. F. Chem. Rev. 1993, 93, 1825. (f) Marshall, K. M.; Barrows, L. R. Nat. Prod. Rep. 2004, 21, 731. For an extensive list of references to the synthesis of phenanthridines in general see: Patra, P. K.; Suresh, J. R.; Ila, H.; Junjappa, H. Tetrahedron 1998, 54, 10167. (a) Miyaura, N.; Yanagi, T.; Suzuki, A. Synth. Commun. 1981, 11, 513. (b) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457. (a) Kristensen, J. L.; Lyse´n, M.; Vedsø, P.; Begtrup, M. Org. Lett. 2001, 1435. (b) Kristensen, J. L.; Lyse´n, M.; Vedsø, P.; Begtrup, M. Org. Synth. 2005, 81, 134. When 4a was heated in neat morpholine at 225 8C for 1 h, 6 was produced in 78% isolated yield, see Section 4 for details. (a) Meyers, A. I.; Williams, B. E. Tetrahedron Lett. 1978, 3, 223. (b) For a review, see: Reuman, M.; Meyers, A. I. Tetrahedron 1985, 41, 837. DMPUZN,N 0 -dimethyl-N,N 0 -propyleneurea, see: Seebach, D.; Mukhopadhyay, T. Helv. Chim. Acta 1982, 65, 385. At that time there was only a single report in the in the literature describing an unselective ortho-lithiation of 3-cyanopyridine: Pletnev, A. A.; Tian, Q.; Larock, R. C. J. Org. Chem. 2002, 67, 9276. Recently a more general study
10. 11.
12.
13.
appeared describing the lithiation of cyanopyridines, see: Cailly, T.; Fabis, F.; Lemaıˆtre, S.; Bouillon, A.; Rault, S. Tetrahedron Lett. 2005, 46, 135. For a recent review of heterocyclic boronic acids see: Tyrrell, E.; Brookes, P. Synthesis 2004, 4, 469. Recently the addition of CuI was reported to be crucial in the coupling of other pyridylboronic derivatives: (a) Hodgson, P. B.; Salingue, F. H. Tetrahedron Lett. 2004, 45, 685. (b) Gros, P.; Doudouh, A.; Fort, Y. Tetrahedron Lett. 2004, 45, 6239. Fluoride activation in Suzuki–Miyaura couplings, see: Wright, S. W.; Hageman, D. L.; McClure, L. D. J. Org. Chem. 1994, 59, 6095. Alternative synthesis of 7 from 3-bromo-2-chloropyridine, see Section 4 for details.
14. Penney, J. M. Tetrahedron Lett. 2004, 45, 2667.